Manufacture of new quinone compounds



amino-quinones are obtain v n H .erto been possible to produce .2:'6 bis ethyleneimin6 pohtai MANUFACTURE ormtw QUINONE COMPOUNDS Adrian Marxer, Basi, Switzerland, assignor to Ciha Pharmaceutical Products, Inc., Summit, N. J., a corpowhich the alkyl residue is, for example, methyl, ethyl,.

pr ps or. b tr T e am qund n e to b cludedwithimthesgopeofthis invention are primarily the quinones of the formulae:

and

The new 'eompean exhibit bactericidal, properties and are active against amoebaefor example Eri'tar'izoeba histolyti c'a. ,7 U I Itis known: that by reaction of quinone's with amines T .fi w i r it s neth bnzo'quinones by thismetlfod. When, for example, 2:6-

dichloro p benzoquino'ne is reacted with, ethyleneiinine,

32 6 bis ethyleneiniinoi chlQ'ro-p-benzoquinbrie is obtained [see Petersen, "Gauss and Urbschat, Angewandte Cher'hie 67, 227, 1955 p The {ne 2:6 bis-ethyleneimino-p-benzoquinones are ned when 3:S diliaIogeiiQPbenzthqtlifliiris, which tached to aesrbbn atom, one lower alkyl 'residuefprefmi filial n -po' ns th tifie hydrbxylr 2,841,581 Patented July 1, 1958 "ice . f2. erably a methyl residue. If desired the halogen atoms in the resulting 2:6-bis-ethyleneimino-3:S-dihalogeno-pbenzoquinones are replaced by lower alkoxy or lower alkyl mercapto groups.

The reaction is-preferably carried out in a solvent, such as dioxane or ethyl, 'isopropyl or butyl alcohol, isopropyl ether or the like, and if desired in the presence of condensing agents such as tertiary bases. The replacement of thehalogenatoms by lower alkoxy or lower alkyl mercapto groups can be carried out in the customary manner, for example by reaction with corresponding alkali alcoholates, such as sodium alcoholates, or alkali mercaptides, preferably at room temperature.

, The quinones of the present invention can he used as 'bactericides "and also as "medicaments especially in treatses caused by amoeb ae, for example in the form o p I ac'eutical preparations. These contain the specified compounds in admixture with a pharmaceutical organic or inorganic carrier material suitable for enteral, parenteral or local "administration. As carriers there are concerned such substances as do not react with the he "compounds, as 'for'exampl'e gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol or other known medicament carriers. The pharmaceudeal-preparations can be made up in the form, for example of tablets, dragees, powders, salves, creams, suppositories or in liquid form as solutions, suspensions or emulsions. If desired, they are sterilized and/or contain auxiliary substances, such as preserving, stabilizing, wetting or emulsifying agents. They can also contain other therapeutically valuable substances.

The following examples illustrate the invention:

mg disea Example 1 48.9 grams of 3:5-dibromo-2 ;o-dimethoxy-p-benzoquinone are dissolved in 600' cc. of dioxane. To the solution is added dropwise at room temperature a mixture ersazsigr ms of t t'ri'ethylamin'e a'n'd'l3.6 grams of ethyleneimine in 10000. of dioxane. The whole is then stirred for 12 hours at room temperature. The separated vio'let 'r'ieedles of 3g5-dibromo-2:G-bis-tethyleneimino-pben'zoquino'ne of the formula:

are filtered with suction. concentration, a further quantity of the compound is obtained, which after recrystallization from chloroformmethanol melts at C. with decomposition.

Example 2 guinone are introduced" into a solution of 5 grams of sodium'in 250 cc. of absolute alcohoL'an internal tem- Frjom tlie mother liquor, on

tained of 3 :S-die't'hoxy-Z:6-bis-ethyleneimino-p-benzoquinone of melting .point 119 C. It possesses the for- If in the above reaction the quantity of sodium is increased to 7:5 grams, the yield can be further raised.

Example 3 A solution of 2.3 grams of sodium in 100 cc. of absolute alcohol is cooled and mixed with 6.5 grams of ethyl mercaptan. While this solution is being cooled slightly, 17.4 grams of 3:'5-dibromo 2:6-bis-ethyleneimino-p-benzoquinone are introduced in such mnner that the temperature does not exceed 26 C. The whole is stirred at room temperature for 12 hours and then mixed with 400 cc. of water. After some stirring, the yellowbrown suspension is filtered with suction. The residue is boiled with 200 cc. of alcohol, some violet starting material is separated, and the mother liquor concentrated by evaporation, whereupon the yellow-green crystals of 3:5 bis ethylmercapto 2:6 bis ethyleneimino-p-benzoquinone of the formula:

HgO\ II /CH5 20 CH: H 053 SOZHI are obtained. The substance melts at 8689 C.

Example 4 65.2 grams of 3:5-dibromo-2:6-dimethoxy-p-benzoquinone are dissolved in 600 cc. of dioxane, and to this solution there is added dropwise a mixture of 44.5 grams of triethylamine and 24.0 grams of C-methyl-ethyleneimine in 100 cc. of dioxane. The temperature is maintained at 50 C. whilst the mixture is added and for a further 5 hours. The clear solution is evaporated to dryness under reduced pressure, the crystalline residue is allowed to stand with methanol, filtered with suction to remove the methanol and recrystallized from hot methanol. The resulting 3:5-dibromo-2:6-bis-methylethyleneimino-p-benzoquinone melts at 128 C. and decomposes with explosion at 195 C. It has the formula:

Etc-H OH-CH| Br Br Example 18.8 grams of the 32S-dibromo-Z:6-bis-methylethyleneimino-p-benzoquinone obtainable according to Example 4 are added to a solution of 2.3 grams of sodium in 180 cc. of absolute methanol. The internal temperature increases from 24 to 29 C. After stirring for eight hours at room temperature, the mixture is filtered, the mother liquor evaporated to dryness under reduced pressure and the residue heated to the boil with 200 cc. of benzene. Insoluble sodium bromide which is formed is filtered off, the benzene solution is concentrated to a small volume and petroleum ether is added gradually, violet 4 crystals of 3 :S-dimethoxy-Z:6-bis-methylethyleneiminop-benzoquinone of melting point C. being obtained. The compound has the formula:

Example 6 18.8 grams of 3z5-dibromo 2z'o-bis-methylethyleneimino-p-benzoquinone obtainable according to Example 4 are added to a solution of 2.3 grams of sodium in cc. of absolute ethyl alcohol and worked up as described in Example 5. Violet crystals of the formula:

0 HaC\ ll /CH: N i i CHr-HC CHI-CH: H50 0 OUzHl are obtained. On being heated rapidly, the resulting 3 :5 -diethoxy*2 6-bis-methylethyleneimino-p-benzoquinone decomposes at 93 C.

What is claimed is:

1. 2:-bis-ethyleneimino-p-benzoquinones wherein the 2- and 6-positions each contain a member of the group consisting of unsubstituted ethyleneimino and mono-lower alkyl-ethyleneimino radicals and wherein the 3- and S-positions are substituted by a member of the group consisting of halo, lower. alkoxy and lower alkyl mercapto radicals.

2. A 3:5-dihalo-2:6-bis-(lower alkyl-ethyleneimino)-pbenzoquinone.

3. A 3 :S-di-lower a1koxy-2:6-bis-(lower alkyl-ethyleneimino)-p-benzoquinone.

4. The new compound 3:S-dibromo-Z:6-bis-ethyleneimino-p-benzoquinone.

5. The new compound 3:5-diethoxy-2:6-bis-ethyleneimino-p-benzoquinone.

6. The new compound 3:S-bis-ethylmercapto-Z:6-bisethyleneimino-p-benzoquinone.

7. The new compound 3:5-dimethoxy-2z6-bis-methylethyleneimino-p-benzoquinone.

8. The new compound 3:5-diethoxy-2:6wbis-methylethyleneimino-p-benzoquinone.

9. The new compound 3:5-dibromo-2:6-bis-methyl ethyleneimino-p-benzoquinone.

10. A process for the manufacture of new quinone compounds which comprises the step of treating a 3:5-dihalogeno-p-benzoquinone wherein each of the 2- and 6-positions contains a member of the group consisting of etherified hydroxyl and mercapto substituents, with a member of the group consisting-of unsubstituted ethyleneirnine and ethyleneirnine containing a mono-lower alkyl residue attached to a carbon atom and treating the resulting compound with an alkali lower alcoholate.

11. A process as set forth in claim 10 wherein the reaction is carried out with ethyleneirnine.

12. A process as set forth in claim 10, wherein the reaction is carried out with C-methyl-ethyleneimine.

13. A process for the manufacture of new quinone compounds which comprises the step of treating a 3:5-dihalogeno-p-benzoquinone wherein each of the 2- and 6-positi0ns contains a member of the group consisting of etherified hydroxyl and mercapto substituents, with a member of the group consisting of unsubstituted ethyleneirnine and ethyleneirnine containing a mono-lower alkyl residue attached to a carbon atom.

14. A process which comprises the step of treating 3:5-dibrorno-2:rlimethoxy-p-benzoquinone with ethyl- 5 I 6 eneimine in the presence of an organic solvent and a References Cited inthe file of this patent ternary base- UNITED STATES PATENTS 15. A process whlch compnses the step of treatmg 3:S-dibromo-Z:6-bis-ethyleneimino-p-benzoquinone with 2770617 Mal-Ker 1956 an alkali lower alcoholate. 5 OTHER REFERENCES A Pmcess .Which P the Step of treating Peterson et aL: Andewandte Chemie 67 217-231 3z5-dlbromo-2:6-b1s-ethyIene1m1no-p-benz0quinone with (1955) 7 an alkali lower mercaptidein the presence of an organic solvent. 

1. 2:6-BIS-ETHYLENEIMINO-P-BENZOQUINONES WHEREIN THE 2- AND 6-POSITIONS EACH CONTAIN A MEMBER OF THE GROUP CONSISTING OF UNSUBSTITUTED ETHYLENEIMINO AND MONO-LOWER ALKYL-ETHYLENEIMINO RADICALS AND WHEREIN THE 3- AND 5-POSITIONS ARE SUBSTITUTED BY A MEMBER OF THE GROUP CONSISTING OF HALO, LOWER ALKOXY AND LOWER ALKYL MERCAPTO RADICALS. 